EA032195B1 - Новые производные азабензимидазола - Google Patents
Новые производные азабензимидазола Download PDFInfo
- Publication number
- EA032195B1 EA032195B1 EA201600113A EA201600113A EA032195B1 EA 032195 B1 EA032195 B1 EA 032195B1 EA 201600113 A EA201600113 A EA 201600113A EA 201600113 A EA201600113 A EA 201600113A EA 032195 B1 EA032195 B1 EA 032195B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pyridin
- furan
- chloro
- yloxy
- imidazo
- Prior art date
Links
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical class C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 284
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 16
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 14
- -1 cyclohexinyl Chemical group 0.000 claims description 444
- 238000000034 method Methods 0.000 claims description 363
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 182
- 150000003839 salts Chemical class 0.000 claims description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 43
- 201000010099 disease Diseases 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 28
- 125000004076 pyridyl group Chemical group 0.000 claims description 21
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 208000008589 Obesity Diseases 0.000 claims description 17
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- 102000004877 Insulin Human genes 0.000 claims description 15
- 108090001061 Insulin Proteins 0.000 claims description 15
- 229940125396 insulin Drugs 0.000 claims description 15
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 239000000969 carrier Substances 0.000 claims description 8
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 8
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 7
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
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- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 239000003472 antidiabetic agent Substances 0.000 claims description 5
- 229940125708 antidiabetic agent Drugs 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims 3
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims 2
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 abstract description 47
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- 238000001819 mass spectrum Methods 0.000 description 192
- 239000000543 intermediate Substances 0.000 description 148
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 128
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- 239000000203 mixture Substances 0.000 description 110
- UBVWYDZEQJSKOY-UHFFFAOYSA-N 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-ol Chemical compound C1COC2C(O)COC21 UBVWYDZEQJSKOY-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
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- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 39
- DTGSFFWQUULHIF-UHFFFAOYSA-N imino-dimethyl-oxo-$l^{6}-sulfane Chemical compound CS(C)(=N)=O DTGSFFWQUULHIF-UHFFFAOYSA-N 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 28
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
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- 239000012267 brine Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 125000005555 sulfoximide group Chemical group 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 229910052786 argon Inorganic materials 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 16
- 239000000872 buffer Substances 0.000 description 15
- 230000001404 mediated effect Effects 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- 230000004913 activation Effects 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 11
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- XQMNBTZLYOOAGA-UGESXGAOSA-N (3r,3ar,6r,6ar)-6-[[6-chloro-5-(4-phenylphenyl)-1h-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol Chemical compound O([C@H]1[C@H]2OC[C@H]([C@H]2OC1)O)C(NC1=CC=2Cl)=NC1=NC=2C(C=C1)=CC=C1C1=CC=CC=C1 XQMNBTZLYOOAGA-UGESXGAOSA-N 0.000 description 9
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 4
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Obesity (AREA)
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- Heart & Thoracic Surgery (AREA)
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- Urology & Nephrology (AREA)
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- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13176929 | 2013-07-17 | ||
| PCT/EP2014/065004 WO2015007669A1 (en) | 2013-07-17 | 2014-07-14 | New azabenzimidazole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201600113A1 EA201600113A1 (ru) | 2016-07-29 |
| EA032195B1 true EA032195B1 (ru) | 2019-04-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| EA201600113A EA032195B1 (ru) | 2013-07-17 | 2014-07-14 | Новые производные азабензимидазола |
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| Country | Link |
|---|---|
| US (1) | US9492436B2 (pl) |
| EP (1) | EP3022210B1 (pl) |
| JP (1) | JP6491656B2 (pl) |
| KR (1) | KR20160033749A (pl) |
| CN (1) | CN105377857B (pl) |
| AR (1) | AR096936A1 (pl) |
| AU (1) | AU2014292236B2 (pl) |
| CA (1) | CA2918401A1 (pl) |
| CL (1) | CL2016000026A1 (pl) |
| DK (1) | DK3022210T3 (pl) |
| EA (1) | EA032195B1 (pl) |
| ES (1) | ES2669543T3 (pl) |
| HU (1) | HUE038261T2 (pl) |
| MX (1) | MX359040B (pl) |
| PH (1) | PH12016500092A1 (pl) |
| PL (1) | PL3022210T3 (pl) |
| TR (1) | TR201806860T4 (pl) |
| TW (1) | TW201546076A (pl) |
| UY (1) | UY35668A (pl) |
| WO (1) | WO2015007669A1 (pl) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2015309863B2 (en) | 2014-08-27 | 2019-12-05 | Shionogi & Co., Ltd. | Azaindole derivative having AMPK-activating effect |
| JPWO2016068099A1 (ja) | 2014-10-28 | 2017-08-10 | 塩野義製薬株式会社 | Ａｍｐｋ活性化作用を有する複素環誘導体 |
| US10053471B2 (en) * | 2015-01-16 | 2018-08-21 | Boehringer Ingelheim International Gmbh | Azabenzimidazole derivatives |
| EP3421467A4 (en) | 2016-02-26 | 2019-08-07 | Shionogi & Co., Ltd | 5-PHENYLAZAINDOLE DERIVATIVE HAVING AMPK ACTIVATION EFFECT |
| JPWO2017200068A1 (ja) | 2016-05-20 | 2019-03-22 | 塩野義製薬株式会社 | Ａｍｐｋ活性化作用を有する５−置換ベンズイミダゾールおよび５−置換アザベンズイミダゾール誘導体 |
| UY38941A (es) | 2019-11-11 | 2021-06-30 | Pi Industries Ltd | Nuevas sulfiliminas o sulfoximinas que contienen compuestos heterocíclicos fungicidas |
| KR20230012597A (ko) | 2020-05-19 | 2023-01-26 | 칼리오페, 인크. | Ampk 활성화제 |
| JP2023531726A (ja) | 2020-06-26 | 2023-07-25 | キャリーオペ，インク． | Ａｍｐｋアクチベーター |
Citations (2)
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| WO2008008895A1 (en) * | 2006-07-13 | 2008-01-17 | Smithkline Beecham Corporation | Gpr119 agonists for the treatment of diabetes and related disorders |
| WO2012116145A1 (en) * | 2011-02-25 | 2012-08-30 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
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| CN103209981B (zh) | 2010-09-10 | 2016-12-28 | 盐野义制药株式会社 | 具有ampk活化作用的杂环稠合咪唑衍生物 |
| US9556193B2 (en) * | 2012-08-22 | 2017-01-31 | Merck Shapr & Dohme Corp. | Benzimidazole hexahydrofuro[3,2-b]furan derivatives |
| WO2014031515A1 (en) * | 2012-08-22 | 2014-02-27 | Merck Sharp & Dohme Corp. | Novel azabenzimidazole hexahydrofuro[3,2-b]furan derivatives |
| WO2014069426A1 (ja) * | 2012-10-31 | 2014-05-08 | 塩野義製薬株式会社 | Ａｍｐｋ活性化作用を有するベンズイミダゾールおよびアザベンズイミダゾール誘導体 |
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- 2014-07-14 DK DK14738531.4T patent/DK3022210T3/en active
- 2014-07-14 KR KR1020167004147A patent/KR20160033749A/ko not_active Application Discontinuation
- 2014-07-14 CN CN201480040799.5A patent/CN105377857B/zh active Active
- 2014-07-14 EP EP14738531.4A patent/EP3022210B1/en active Active
- 2014-07-14 WO PCT/EP2014/065004 patent/WO2015007669A1/en active Application Filing
- 2014-07-14 TR TR2018/06860T patent/TR201806860T4/tr unknown
- 2014-07-14 AU AU2014292236A patent/AU2014292236B2/en not_active Ceased
- 2014-07-14 HU HUE14738531A patent/HUE038261T2/hu unknown
- 2014-07-14 MX MX2016000547A patent/MX359040B/es active IP Right Grant
- 2014-07-14 EA EA201600113A patent/EA032195B1/ru not_active IP Right Cessation
- 2014-07-15 US US14/331,359 patent/US9492436B2/en active Active
- 2014-07-16 TW TW103124425A patent/TW201546076A/zh unknown
- 2014-07-16 AR ARP140102623A patent/AR096936A1/es unknown
- 2014-07-17 UY UY0001035668A patent/UY35668A/es unknown
-
2016
- 2016-01-07 CL CL2016000026A patent/CL2016000026A1/es unknown
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008008895A1 (en) * | 2006-07-13 | 2008-01-17 | Smithkline Beecham Corporation | Gpr119 agonists for the treatment of diabetes and related disorders |
| WO2012116145A1 (en) * | 2011-02-25 | 2012-08-30 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
Also Published As
| Publication number | Publication date |
|---|---|
| UY35668A (es) | 2015-01-30 |
| HUE038261T2 (hu) | 2018-10-29 |
| WO2015007669A1 (en) | 2015-01-22 |
| EP3022210A1 (en) | 2016-05-25 |
| MX359040B (es) | 2018-09-13 |
| PL3022210T3 (pl) | 2018-08-31 |
| DK3022210T3 (en) | 2018-06-06 |
| US9492436B2 (en) | 2016-11-15 |
| CA2918401A1 (en) | 2015-01-22 |
| CN105377857B (zh) | 2018-04-10 |
| TR201806860T4 (tr) | 2018-06-21 |
| PH12016500092B1 (en) | 2016-04-18 |
| CL2016000026A1 (es) | 2016-08-12 |
| PH12016500092A1 (en) | 2016-04-18 |
| AR096936A1 (es) | 2016-02-10 |
| KR20160033749A (ko) | 2016-03-28 |
| EP3022210B1 (en) | 2018-02-21 |
| AU2014292236A1 (en) | 2016-01-21 |
| JP2016527223A (ja) | 2016-09-08 |
| US20150025065A1 (en) | 2015-01-22 |
| EA201600113A1 (ru) | 2016-07-29 |
| JP6491656B2 (ja) | 2019-03-27 |
| ES2669543T3 (es) | 2018-05-28 |
| MX2016000547A (es) | 2016-04-20 |
| TW201546076A (zh) | 2015-12-16 |
| CN105377857A (zh) | 2016-03-02 |
| AU2014292236B2 (en) | 2018-11-08 |
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| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG TJ TM RU |